Mole-rats are champions of self-preservation, with increased longevity compared with other rodents their size, strong
antioxidant capabilities and specialized defenses against endogenous oxidative stress. However, how the brains of these subterranean mammals handle acute in vivo
hypoxia is poorly understood. This study is the first to examine the molecular response to low
oxygen in six different species of
hypoxia-tolerant mole-rats from sub-Saharan Africa. Protein carbonylation, a known marker of DNA damage (hydroxy-2'-deoxyguanosine), and
antioxidant capacity did not change following
hypoxia but HIF-1
protein levels increased significantly in the brains of two species. Nearly 30
miRNAs known to play roles in
hypoxia tolerance were differentially regulated in a species-specific manner. The
miRNAs exhibiting the strongest response to low
oxygen stress inhibit apoptosis and regulate
neuroinflammation, likely providing neuroprotection. A principal component analysis (PCA) using a subset of the molecular targets assessed herein revealed differences between control and hypoxic groups for two solitary species (Georychus capensis and Bathyergus suillus), which are ecologically adapted to a normoxic environment, suggesting a heightened sensitivity to
hypoxia relative to species that may experience
hypoxia more regularly in nature. By contrast, all molecular data were included in the PCA to detect a difference between control and hypoxic populations of eusocial Heterocephalus glaber, indicating they may require many lower-fold changes in signaling pathways to adapt to low
oxygen settings. Finally, none of the Cryptomys hottentotus subspecies showed a statistical difference between control and hypoxic groups, presumably due to
hypoxia tolerance derived from environmental pressures associated with a subterranean and social lifestyle.